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VCP Promotes Cholangiocarcinoma Development by Mediating BAP1 Ubiquitination-Dependent Degradation

Peiying Zhang1, Xiangning Liu1, Yue Liu1

  • 1Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Cancer Science
|March 23, 2025
PubMed

Insights

Researchers identified Valosin-containing protein (VCP) as a target for Cholangiocarcinoma (CCA) treatment. Blocking VCP inhibits tumor growth by preventing the degradation of the tumor suppressor BAP1, offering a new therapeutic strategy for CCA.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cholangiocarcinoma (CCA) is a highly malignant cancer with limited effective treatment options.
  • Current targeted therapies for CCA, like Pemigatinib and Ivosidenib, benefit only a subset of patients (~30%) with specific mutations (FGFR, IDH1/2).
  • Downregulation of the BAP1 tumor suppressor is common in CCA and linked to poor prognosis, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the tumor-suppressive role of BAP1 in Cholangiocarcinoma.
  • To identify upstream regulators of BAP1 protein homeostasis in CCA.
  • To evaluate the therapeutic potential of targeting VCP (Valosin-containing protein) in CCA treatment.

Main Methods:

  • Demonstrated the tumor-suppressive functions of BAP1 in CCA models.
  • Identified VCP as a key regulator of BAP1 protein levels.
  • Investigated the mechanism of VCP-mediated BAP1 degradation via the ubiquitin-proteasome pathway.
  • Assessed the anti-tumor effects of VCP inhibitors in CCA cell lines.

Main Results:

  • VCP binds to BAP1, promoting its ubiquitination and degradation through the ubiquitin-proteasome pathway, which drives CCA cell proliferation and inhibits apoptosis.
  • VCP inhibition blocked BAP1 degradation, leading to reduced CCA cell growth and increased apoptosis.
  • These findings elucidate a novel mechanism for BAP1 downregulation in CCA.

Conclusions:

  • Aberrant low expression of BAP1 in CCA is mediated by VCP-induced degradation.
  • VCP acts as a crucial upstream regulator of BAP1 protein homeostasis in CCA.
  • VCP inhibitors demonstrate anti-tumor efficacy in CCA by restoring BAP1 levels, presenting VCP as a promising therapeutic target for CCA.
Keywords:
BAP1VCPcell apoptosischolangiocarcinomaubiquitination

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